Pre-exposure prophylaxis and treatment can lower HIV infection rates but nearly two million new infections still occur worldwide each year. A vaccine that can elicit long-lived protective immunity against HIV infection offers the best prospect to end the AIDS epidemic. While no licensed HIV vaccine is available, the modest efficacy observed in the RV144 Thai Trial raises hope that a preventive vaccine is possible. To improve on this efficacy, a deeper understanding of the underlying immune mechanism of vaccine protection is crucial. Our proposed studies aim at generating critical insights on how to improve anti-HIV T cell function, induce enhanced immune potency and durability, and develop paths to elicit broad neutralizing antibodies. We are in a unique position to address these topics with access to an exceptional set of samples from several HIV vaccine trials and well- characterized HIV infection cohorts. Our proposed studies include assessment of the kinetics of the vaccine- induced immune response in relevant anatomic compartments (lymph nodes, bone marrow and gut) and access to cutting edge analytical methods to generate linked datasets that are ideally suited for our proposed, comprehensive systems biology approach. Our project team is uniquely suited to conduct these studies, as leaders and well-established collaborators focused on HIV vaccine research, translational immunology, systems approaches to understand immunological memory, and immune correlates analyses. We expect that our work will reveal testable hypotheses on the underlying mechanistic interplay between key components of the innate and adaptive immune response that are responsible for protection against HIV by vaccination.